The overall objective of this DISCOVER Center is to investigate the mechanisms by which traffic-related air pollution causes myocardial infarction and other cardiovascular diseases, by integrating a diverse set of research approaches. Air pollution exposures have been consistently associated with cardiovascular disease. A growing literature indicates that the major source of variation in air pollution's cardiovascular health effects is from exposure to traffic. Diesel exhaust is an excellent model exposure. The closely linked suite of activities in this DISCOVER Center will attempt to understand the mechanisms (molecular mechanisms that cause vasoconstriction and acceleration of atherosclerosis) underlying exposure-related effects, and use environmental exposures to understand basic mechanisms regarding vascular biology. The studies will exploit exposure contrasts in experimental and epidemiological studies through advanced exposure assessment methods, and genetic diversity in both human and animal studies, to advance our aims. The application brings together a cohesive group of five projects (two patient-oriented and three basic mechanistic studies) and three cores, Administrative, Exposure Science, and Biostatistics and Bioinformatics. Project 1 investigates the mechanism underlying vascular response in humans following controlled exposure to diesel exhaust;Project 2 studies genetic modifiers on the effect of traffic-related air pollution on vascular response and atherosclerosis in a population-based human observational study. Project 3 investigates the role of systemic inflammation in the vascular response to diesel exhaust. Project 4 investigates the impact of diesel exhaust exposure on myocardial injury and apoptosis. Project 5 investigates reactive oxygen species and oxidative stress in the vascular response to diesel exhaust. Through this research, the investigators will develop knowledge that can be used to develop preventive and therapeutic strategies. INTEGRATED (clinical and basic) and INTERDISCIPLINARY NATURE OF PROGRAM